1. Field of the Invention
The present invention relates to novel trichothecene derivatives, to processes for their production and to their use as antitumor agents for the inhibition of malignant tumors in mammals.
2. Description of the Prior Art
The trichothecene derivatives of the present invention all contain a 9,10 double bond and a 12,13-epoxy function. The basic skeleton and numbering system for this class of trichothecenes is shown below. ##STR1## Various examples of both naturally occurring and semi-synthetic compounds of this class have been described in the literature. Illustrative of the more relevant publications are the following:
1. The compound anguidine (also called diacetoxyscirpenol) having the formula ##STR2## is disclosed as an antitumor agent in U.K. Pat. No. 1,063,255. Phase I clinical trials of anguidine in the United States have been reported in Proc. Amer. Assoc. Cancer Res. 17:90 (1976) and Proc. Amer. Assoc. Cancer Res. 18:296 (1977). Also disclosed (at least generically) are various derivatives of anguidine such as anguidol (also called scirpentriol or 3.alpha.,4.beta.,15-trihydroxy-12,13-epoxytrichothec-9-ene), monodesacetylanguidine (presumably 15-acetoxy-3.alpha.,4.beta.-dihydroxy-12,13-epoxytrichothec-9-ene or monoacetoxyscirpendiol) and esters of anguidine, anguidol and monodesacetylanguidine.
Monoacetoxyscirpenol and various esters of scirpentriol are also disclosed in J. Agric. Food Chem. 24(1): 97-103 (1976) as mycotoxins.
2. Japanese Published Applications Nos. J4 9,134,891 and J4 9,134,892 disclose T2 and HT2 toxins of the formula ##STR3## wherein R is --OH or ##STR4## The compounds are said to be useful as antiviral agents.
3. U.S. Pat. No. 4,129,577 discloses anguidine derivatives of the formula ##STR5## wherein R.sub.1 is H or ##STR6## and R is an alkyl or aromatic group or is an acyl group ##STR7## in which R.sup.1 is an aliphatic, cycloaliphatic or aromatic group or a carbamate group --CONH-R.sup.1. The compounds are useful as cytotoxic agents.
4. U.S. Pat. No. 3,428,652 discloses anguidine derivatives of the formula ##STR8## wherein R.sub.1 is H and R.sub.2 is methyl or, R.sub.1 and R.sub.2 together represent propylene, and Hal is Cl, Br or I. The compounds are reported to have antitumor activity.
5. Toxins isolated from culture filtrates of F. scirpi and having the formula ##STR9## are disclosed in J. Chem. Soc (C), 375 (1970).
6. Trichothecene derivatives of the formula ##STR10## wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are -OH or -OCOCH.sub.3 are disclosed in Biochemical Pharmacology 24:959-962 (1972) as having larvicidal activity. The degree of activity is said to be greatest in the compound where R.sup.1 .dbd.R.sup.2 .dbd.R.sup.3 .dbd.R.sup.4 .dbd.OH and least in the fully acetylated compound. It is suggested in the publication that the order of cytotoxic activity in this series is the same as the order of larvicidal activity.
7. The 12,13-epoxytrichothecenes of the general formula ##STR11## wherein R.sup.1 and R.sup.3 are H, OH or esterified OH and R.sup.2 is OH, .dbd.O or esterified OH are described in Biochemical and Biophysical Research Communications 57(3):838-844 (1974)as inhibitors of protein synthesis. The publication indicates that substitution of a carbonyl group at the C-8 position of the above compounds results in a moderate loss of activity and that substitution of a carbonyl group at C-4 results in complete loss of activity.
8. Helvetica Chimica Acta 48:962-988 (1965) discloses the 4-keto compound of the formula ##STR12## the 3-keto compounds of the formulae ##STR13## and the oxime compound of the formula ##STR14##
The above-mentioned 3-keto diester is also disclosed in J. Chem. Soc. Chem. Comm., 1965, pg. 26-27 and in J. Chem. Soc. (C), pg. 369-375 (1970). None of the publications provide any information as to biological properties of the keto or oxime compounds.